Tuberculosis (TB), is a disease mainly caused by Mycobacterium tuberculosis (Mtb). Besides Mtb, other TB-causing mycobacteria include M. africanum, M. bovis, M. canetti, M. caprae, M. microti, M. mungi and M. pinnipedii. Together these mycobacteria are referred as the mycobacterium tuberculosis complex (MTBC).
The complete sequencing of the Mtb genome was completed more than 10 years ago. The last decade has seen major progress in the understanding of TB and, as a result, several therapeutic leads have been identified to help contain the infection. Recently, TMC207 (bedaquiline) was the first new anti-TB agent to be approved in over 40 years. However, TB still remains persistently prevalent, resulting in approximately 2 million deaths every year. The emergence of multi drug resistant (MDR), extensive drug resistant (XDR) and, recently, totally drug resistant strains further emphasizes the desperate, growing need for new anti-TB agents.
The discovery of 1,3-Benzothiazin-4-ones (BTZs), especially BTZ043 (compound 1, FIG. 1) as a potent agent for the treatment of tuberculosis, led subsequently to the identification of several other classes of nitroaromatic compounds as anti-TB agents. BTZ043 and its closest congener PBTZ169 (compound 2, FIG. 1) and analogs have been shown to kill Mtb in vitro, ex vivo, and in mouse models of TB. Both of these agents were shown to be a suicide inhibitor of DprE1, a key enzyme of the cell wall assembly for mycobacteria.
The detailed mode of suicide inhibition of 1 and 2 was elucidated and it was shown to involve the reductive activation of the nitro group into a nitroso intermediate (see FIG. 2A, compound 4) which further covalently inactivates DprE1 (FIG. 2A, compound 5).